Integrins are heterodimeric cell adhesion receptors composed of two subunits, α and β. The integrin αvβ6 is a fibronectin and tenascin receptor expressed predominantly by epithelial cells. In healthy adult primate tissues, β6 mRNA and protein are rarely detected, although β6 is expressed during fetal development, wound healing, and in some epithelial tumors. When the β6 subunit is expressed in a colon carcinoma cell line, from which it is normally absent, expression of the subunit confers an enhanced ability to proliferate. An 11 amino acid COOH-terminal region, unique to the β6 subunit, is required for the proliferation-enhancing activity of the αvβ6 integrin (Agrez et al. J. Cell. Biol. 127:547-556 (1994). β6 expression is induced in type II aveolar epithelial cells during injury caused by injection of live bacteria, and β6 expression is observed at focal sites of subclinical inflammation, as well as in a variety of clinical specimens from patients with chronic or acute inflammation of the lungs or kidneys (Breuss et al. J. Cell Sci. 108:2241-2251 (1995).
Huang et al. (T. Cell Biol. 133:921-928 (1996)) disclosed mice homozygous for a null mutation in the gene encoding the β6 subunit had juvenile baldness associated with infiltration of macrophages into the skin, and accumulated activated lymphocytes around conducting airways in the lungs.
Pulmonary fibrosis is a common disorder thought to be due to the destructive effects of products released from leukocytes (see, for example, Marshall et al., Int. J. Biochem. Cell Bio. 29:107-120 (1997)). Bleomycin-induced lung injury and pulmonary fibrosis are associated with and may depend upon the recruitment and activation of lymphocytes (Schrier, D. J. et al., Am. T. Pathol. 116:270-278 (1984)). Among proposed therapies for parenchymal lung injury and pulmonary fibrosis is the use of “anticytokine” therapeutic approaches (Coker et al. Thorax 52(2):294-296 (1997)).
However, current therapies for acute lung injury and pulmonary fibrosis are largely inadequate (see, for example, King et al., “Idiopathyic Pulmonary Fibrosis and other Interstitial Lung Diseases of Unknown Etiology,” in Textbook of Respiratory Medicine, Murray and Nadel, eds., W. B. Saunders, Philadelphia, Pa., pp. 1827-1839 (1994)). Thus, a need exists for therapies for acute lung injury and pulmonary fibrosis. This need and others are addressed by the instant invention.